July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Evidence of somatic mitochondrial DNA mutations in primary open angle glaucoma
Author Affiliations & Notes
  • Neeru Amrita Vallabh
    University of Liverpool, Liverpool, United Kingdom
  • Brian Lane
    University of Liverpool, Liverpool, United Kingdom
  • David A Simpson
    Queens University Belfast, United Kingdom
  • Marc Fuchs
    Queens University Belfast, United Kingdom
  • Anshoo Choudhary
    University of Liverpool, Liverpool, United Kingdom
  • David Criddle
    University of Liverpool, Liverpool, United Kingdom
  • Robert Cheeseman
    Royal Liverpool Hospital, United Kingdom
  • Colin Willoughby
    Ulster University, United Kingdom
  • Footnotes
    Commercial Relationships   Neeru Vallabh, None; Brian Lane, None; David Simpson, None; Marc Fuchs, None; Anshoo Choudhary, None; David Criddle, None; Robert Cheeseman, None; Colin Willoughby, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1613. doi:
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    • Get Citation

      Neeru Amrita Vallabh, Brian Lane, David A Simpson, Marc Fuchs, Anshoo Choudhary, David Criddle, Robert Cheeseman, Colin Willoughby; Evidence of somatic mitochondrial DNA mutations in primary open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1613.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The aim of this study was to determine the role of mitochondrial DNA (mtDNA) mutations in primary open angle glaucoma (POAG) using massively parallel sequencing.

Methods : POAG patients and disease-negative controls were recruited and underwent ophthalmic assessment and DNA extraction from blood leucocytes. In a subset of this cohort Tenon fibroblasts were harvested at the time of ocular surgery, cultured and DNA was extracted. The mitochondrial genome was amplified in two overlapping fragments (9289bp and 7626bp) by long-range PCR and underwent massively parallel sequencing on the Illumina NextSeq 500. Variant annotation and heteroplasmy levels were analysed using the mtDNA-Server (mtdna-server.uibk.ac.at). Known mtDNA, polymorphisms and novel variants were filtered using MITOMAP and control data.

Results : 101 POAG patients and 83 disease-negative controls were recruited; Tenon fibroblasts were acquired at the time of ocular surgery from a sub-set of the study group: POAG patients (n=29) and control (n=13). Analysis of mtDNA mutations in the blood demonstrated there were no significant differences (Fisher exact test at p<0.05) in novel or previously disease associated non-synonymous variants in POAG cases versus controls. There was a significant difference in novel mtDNA variants in the POAG Tenon fibroblasts versus control patient fibroblasts (p<0.05). When comparing the paired samples (blood and Tenon fibroblast mtDNA) there were 2 novel potentially-pathogenic variants in the control tissue that were not seen in the control blood or glaucoma blood or Tenon fibroblasts; in the POAG subset there were 11 novel potentially pathogenic, 9 variants of unknown significance and 4 benign novel variants that were not seen in the POAG blood or control blood or Tenon fibroblasts. Only 1 potentially pathogenic variant (m.8801T>C) was found in paired sample (blood/Tenon fibroblast) in one POAG subject.

Conclusions : The high frequency of novel mtDNA variation in the Tenon fibroblasts which were absent from blood derived mtDNA in POAG supports the concept that somatic mtDNA mutation occurs in POAG. Mutations are acquired locally in ocular tissue in POAG and are not inherited or germline. Somatic mtDNA mutations in POAG are likely secondary to the local pathophysiological environment and elucidating the mechanism of induced mtDNA damage may offer novel therapeutic opportunities.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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